Congenital Cytomegalovirus (CMV) infection is a leading cause of sensorineural hearing loss (SNHL) in children. Among the approximately 40,000 infants born with congenital CMV each year, only ~10% develop SNHL. The variable penetrance of SNHL has been argued to result from differences in host responses to this virus. However, CMV is a complex virus with well documented genetic and phenotypic variability among clinical CMV strains. We hypothesize that specific virus-encoded functions are responsible for an adverse outcome of intrauterine CMV infection and the variability in disease could be reflected in the diversity of viral genotypes and therefore, the phenotypic variability of CMV isolates. We propose several interrelated experimental approaches to investigate the role of genetically unique strains of CMV in the development of SNHL. Initially, the biological behavior of viruses isolated from infants with and without hearing loss and specific viral genes responsible for this behavior will be characterized. This analysis will include in-vitro replication and viral gene expression in a panel of cell lines and primary cells as a screening assay of viral phenotype. We will also determine if there is an interrelationship between host cell responses and viral gene expression that can be associated with disease phenotype. Finally, the frequency of these gene(s) associated with particular disease phenotype will be defined in a large number of virus isolates from a well characterized population. The candidate's long-term goal is to be a Pediatric Infectious Diseases academician and achieve independence as an investigator to contribute to the field of discovery in CMV related hearing loss. The research environment is ideal with mentors who are leaders in the field of congenital CMV infection. The candidate will have protected time to carry out her research in state of the art laboratory facilities with a wealth of available resources. A structured 5 year plan with intensive didactic component in years 1 and 2, some classes and other educational activities in year 3-5, and a research component emphasized in the final three years is proposed. Relevance: Congenital CMV infection is the leading infectious cause of hearing loss yet, little is known about the pathogenesis of this disease. The proposed research will provide further insight into this process and hopefully, identify markers for the development of SNHL. [unreadable] [unreadable] [unreadable]